first-in-human study of atx-559, an oral inhibitor of dhx9, in patients with advanced or metastatic solid tumors, and molecularly defined cancers

Conditions: Advanced Solid Tumors; Breast Cancer Recurrent; Colorectal Cancer Metastatic; Colon Cancer; Rectal Adenocarcinoma; Endometrial Cancer

Summary: the goal of this study is to identify a safe and tolerated dose of the orally administered dhx9 inhibitor atx-559. in addition, this study will evaluate the pharmacokinetics, pharmacodynamics and preliminary antitumor activity of atx-559 in patients with advanced solid tumors and molecularly defined cancers.

atx-559 is an oral drug that inhibits a protein called dhx9, a multi-functional rna helicase that is involved in the maintenance of genomic stability by resolving dna/rna secondary structures that may lead to dna replication stress and dna damage in certain molecularly defined cancers. atx-559 has been shown preclinically to induce robust anti-tumor activity of a variety of different solid tumors, including models with brca deficiency and microsatellite instability-high (msi-h) and/or deficient mismatch repair (dmmr). this is a first-in-human, phase 1, open-label, single-arm, dose-escalation and expansion study to: evaluate the safety profile of atx-559 and determine the recommended phase 2 dose (rp2d). in addition, the study aims to characterize the pk, pd, and preliminary anti-tumor activity of orally administered atx-559. exploratory objectives include examination of biomarker responses in relationship to atx-559 exposure. patients with molecularly selected locally advanced or metastatic solid tumors (for example, brca1- or brca2-deficient breast cancer and solid tumors with microsatellite instability (msi-h) and/or deficient mismatch repair (dmmr) will be enrolled to preliminarily assess the anti-tumor effect, and further examine the safety and pk of atx-559 at the rp2d.

Eligibility criteria:
key inclusion criteria: * patients with histologically confirmed solid tumors who have locally recurrent or metastatic disease * refractory to or relapsed after all standard therapies with proven clinical benefit, unless as deemed by the investigator, the subject is not a candidate for standard treatment, there is no standard treatment, or the subject refuses standard treatment after expressing an understanding of all available therapies with proven clinical benefit * for the expansion cohorts, participants must have histological confirmation of the specified tumor types: * brca1 or brca2 deficient, her2 negative metastatic breast cancer * dmmr or msi-h with unresectable or metastatic solid tumors * there is no limit to the number of prior treatment regimens * have measurable or evaluable disease * have an eastern cooperative oncology group (ecog) performance status of 0 to 1 key exclusion criteria: * clinically unstable central nervous system (cns) tumors or brain metastasis * any other concurrent anti-cancer treatment * has undergone a major surgery within 3 weeks of starting study treatment * medical issue that limits oral ingestion or impairment of gastrointestinal function that is expected to significantly reduce the absorption of atx-559 * clinically significant (ie, active) or uncontrolled cardiovascular disease * unable to transition off strong or moderate cyp2c8 inhibitors or inducers * pregnancy or intent to breastfeed or conceive a child within the projected duration of treatment other inclusion and exclusion criteria as defined in the study protocol

Keywords: msi-high/dmmr tumors brca1 mutation brca2 mutation dhx9 dmmr deficient mismatch repair microsatellite instability